A study by Oxnard et al using bisulfite sequencing of plasma cell-free DNA to identify methylomic signatures for multicancer detection and tissue of origin found the assay achieved accurate detection of multiple cancers across stages and tissue of origin localization. The targeted methylation assay is now undergoing validation in preparation for prospective clinical investigation as a cancer detection diagnostic tool. These findings were presented at ASCO Breakthrough: A Global Summit for Oncology Innovators (Abstract 44).
Study Background and Methodology
Previous research has shown whole-genome bisulfite sequencing outperformed whole-genome and targeted sequencing approaches for multicancer detection at all cancer stages at high specificity. The current researchers analyzed data from 2,301 participants (1,422 with cancer [> 20 tumor types, all stages] and 879 without cancer) in a prespecified substudy from the Circulating Cell-free Genome Atlas Study, a prospective, multicenter, observational, case-control study with longitudinal follow-up.
Plasma cell-free DNA was subjected to a targeted methylation sequencing assay using high-efficiency methylation chemistry to enrich for methylation targets, and a machine learning classifier determined cancer status and tissue of origin. Observed methylation fragments characteristic of cancer and tissue of origin were combined across targeted regions and assigned a relative probability of cancer and to a specific tissue of origin.
KEY POINTS
- The detection of multiple deadly cancers at all stages using methylation signatures in plasma cell-free DNA was achieved with a single, fixed, low false-positive rate and simultaneously provided accurate tissue-of-origin localization.
- The targeted methylation assay is undergoing validation in preparation for prospective clinical investigation as a diagnostic tool for cancer detection.
Results
Performance was reported at 99% specificity (ie, a combined false-positive rate across all cancer types of 1%), a level required for population-level screening. Across cancer types, sensitivity ranged from 59% to 86%.
Combined cancer detection (sensitivity [95% confidence interval]) was 34% (27%–43%) in stage I disease (n = 151), 77% (70%–83%) in stage II (n = 171), 84% (79%–89%) in stage III (n = 204), and 92% (88%–95%) in stage IV (n = 281). Tissue of origin was provided for 94% of all cancers detected; of these, tissue of origin was correct in > 90% of cases.
“Detection of multiple deadly cancers across stages using methylation signatures in plasma cell-free DNA was achieved with a single, fixed, low false-positive rate, and simultaneously provided accurate tissue of origin localization. This targeted methylation assay is undergoing validation in preparation for prospective clinical investigation as a cancer detection diagnostic,” concluded the study authors.
Disclosure: The research sponsor for this study is GRAIL, Inc. For full disclosures of the study authors, visit coi.asco.org.
